Venlafaxine (Page 3 of 11)

5.2 Potential for Interaction with Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Venlafaxine Extended Release Tablets (venlafaxine hydrochloride) not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI.

5.3 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with Venlafaxine Extended Release Tablets treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) [see Drug Interactions (7.10) ].

The concomitant use of Venlafaxine Extended Release Tablets with MAOIs intended to treat depression is contraindicated [see Contraindications (4) and Warnings and Precautions (5.2)].

If concomitant treatment of Venlafaxine Extended Release Tablets with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.10) ].

The concomitant use of Venlafaxine Extended Release Tablets with serotonin precursors (such as tryptophan supplements) is not recommended [see Drug Interactions (7.10) ].

5.4 Sustained Hypertension

Venlafaxine hydrochloride extended-release capsule treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits) (see Table 2).

An analysis for patients in venlafaxine hydrochloride immediate-release tablet studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for immediate-release venlafaxine hydrochloride (see Table 3).

An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

Table 2: Number (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride Extended-Release Capsule Premarketing Studies by Indication
Major Depressive Disorder (75-375 mg/day) Other Clinical Trials (75-225 mg/day)
19/705 (3) 5/771 (0.6)
Table 3: Incidence (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride Immediate-Release Tablet Studies
Venlafaxine mg/day Incidence
<100 3%
>100 to ≤200 5%
>200 to ≤300 7%
>300 13%

In premarketing major depressive disorder studies, 0.7% (5/705) of the venlafaxine hydrochloride extended-release capsule-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In other clinical studies, 0.6% (5/771) of the venlafaxine hydrochloride extended-release capsule-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1 to 24 mm Hg, SDBP).

Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine hydrochloride extended-release tablets have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.

Elevations in Systolic and Diastolic Blood Pressure

In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean change in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in venlafaxine hydrochloride extended-release capsule-treated patients.

Table 4: Final On-Therapy Mean Changes from Baseline in Supine Systolic and Diastolic Blood Pressure (mm Hg) Results by Indication, Study Duration, and Dose in Placebo-Controlled Trials
Venlafaxine Hydrochloride Extended-Release Capsules mg/day Placebo
≤75 >75
SSBP * SDBP SSBP SDBP SSBP SDBP
*
Supine Systolic Blood Pressure
Supine Diastolic Blood Pressure
Major Depressive Disorder 8-12 weeks -0.28 0.37 2.93 3.56 -1.08 -0.10
Other Clinical Trials 12 weeks -0.29 -1.26 1.18 1.34 -1.96 -1.22

Across all clinical trials, 1.4% of patients in the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups.

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